DE1011877B - Process for the preparation of ª † -oxypropylsulfonium halides - Google Patents

Description

Process for the preparation of γ-oxypropylsulfonium halides Die The invention relates to a process for the production of new γ-oxypropylsulfonium halides.

The compounds according to the invention correspond to the following general formula In this formula, R1 denotes an aryl group, R2 denotes a cycloalkyl, alkyl, aryl or aralkyl group, Rs denotes an alkyl group, R4 denotes an alkyl, aralkyl, alkenyl, alkynyl or phenacyl group and X denotes halogen. Such sulfonium salts are white, generally water-soluble crystalline solid substances.

According to the invention, these compounds are prepared by reacting an S-substituted 3-mercaptopropanol- (1), disubstituted in the l-position, of the formula obtained with an organic halide of the formula R4 X. The S-substituted 3-mercaptopropanol- (1) of the formula II, which is disubstituted in the l-position, is obtained by reacting a B-substituted mercaptopropiophenone of the formula made with a Grignard reagent of the general formula R2 Mg Hai. The p-substituted mercaptopropiophenone of the formula III is prepared by reacting a p-substituted mercaptopropionitrile of the general formula R3-S-CH2-CH2-CN (IV) with a Grignard reagent of the formula RlMgHal.

This synthesis can be represented by the following sequence of reactions: The β-alkyl mercaptopropionitriles used as starting materials in this synthesis are known and can be prepared by reacting alkyl mercaptans with acrylonitrile in the presence of a basic catalyst, as described in the chemical literature. The ß-alkyl mercaptopropiophenones are produced from these nitriles by reaction with a suitable Grignard reagent. The magnesium halide compound of the imine formed can be hydrolyzed to the desired ketone with dilute aqueous mineral acid. The reaction of the fl-alkyl mercaptopropiophenones with a suitable Grignard reagent provides the corresponding disubstituted, S-substituted 3-mercaptopropanol- (1) position. The carbinol can be set free from its magnesium halide compound by treatment with aqueous ammonium chloride solution.

The sulfonium halides are made by reacting the in L-position disubstituted, S-substituted 3-mercaptopropanols- (l) of the specified Composition with alkyl, aralkyl or phenacyl, alkenyl or alkynyl halides manufactured. This reaction is carried out at room temperature, usually in the presence an excess of the halide in solvents such as acetone or ether. However, it can also be carried out in the absence of solvents. The sulfonium halide usually precipitates as a crystalline solid substance. Usually the Implementation when using reactive halides such as methyl iodide, allyl iodide, Propargyl iodide or benzyl bromide is very rapid and is essential in 24 hours completed. If less reactive halides are used, the reaction can take place take a long time to complete.

The compounds of the invention have antispasmodic and antigastrosis secretory properties.

Sulfonium compounds; whose constitution that of those after Process according to the invention preparable sulfonium compounds is analogous already known, so z. B. (2, 2-Diphenyl-2-oxyethyl) -dimethyl-sulfonium iodide and (2-methyl-2-phenyl-2-oxyethyl) -dimethyl-sulfonium iodide. These well-known However, compounds have no or only a very weak spasmolytic and no antigastrosis secretory effect. The compounds obtained according to the invention are, on the other hand, good, in some cases excellent, antispasmodics, and they are useful in their use achievable gastrosecretion inhibition is considerable.

The following examples are intended to explain the present invention in more detail.

Example 1 A solution of 101 parts of fl-methyl mercaptopropionitrile in 300 parts of anhydrous ether is added dropwise with stirring to one of 197 Parts of bromobenzene and 28 parts of magnesium in 350 parts of anhydrous ether Phenylmagnesium bromide solution given.

A solid substance precipitates when the nitrile is added. After completion the addition (1 hour) 210 parts of ether are added, and the suspension is 18 Stirred for hours. Then a cold solution of 275 parts is concentrated dropwise Hydrochloric acid in 350 parts of water was added. A lot of heat develops and the ether is allowed to boil off. The two liquid phases are on the steam bath 1 Stirred for hour, cooled and extracted several times with ether. It falls a considerable one Amount of ether-insoluble smear. After drying the combined ether extracts The solvent is driven off over anhydrous sodium sulfate and the remaining one Oil distilled under reduced pressure. After a short run, it becomes ß-methyl mercaptopropiophenone as a colorless oil from Kr. ,, = 112 to 117 ° intercepted. The yield is 93 parts (53 Ob). The renewed distillation gives a material with a boiling point of l, l = 110 to 115 °, n29 = 1.5687.

A solution of 60 parts of jB-methyl mercaptopropiophenone in 140 parts anhydrous ether is added dropwise with stirring in the usual way from 65 Parts of cyclohexyl bromide and 9.3 parts of magnesium in 300 parts of anhydrous ether Cyclohexylmagnesium bromide solution prepared added. Heat is developed and the rate of addition is adjusted so that the ether is refluxed simmering gently. In a few minutes a gray solid substance will begin to precipitate.

The addition is complete after 70 minutes and the stirring is still 18 Hours continued. Then a solution of 45 parts of ammonium chloride in 150 Parts of water are added, developing heat. The ether phase is separated and combined with an ether extract of the aqueous phase. After drying the combined ethereal solutions over anhydrous sodium sulfate, the solvent is driven off and the remaining oil is distilled under reduced pressure. One receives after a considerable first run 28 parts (32 O / o) 1-cyclohexyl-3-methylmercapto-1 -phenylpropanol- (l) from Kp.l, a = 156 to 165 ". The renewed distillation of a sample yields a material of Kp. ,,, = 150 ".

40 parts of 1-cyclohexyl-3-methylmercapto-1-phenyl-propanol- (l) will be dissolved in 228 parts of methyl iodide. Crystals begin to form within a short time to train.

After standing for 24 hours at room temperature, the solid precipitate becomes the brownish-colored product is filtered off, washed with acetone and ether and air; dries. Washing with acetone almost completely removes the color. The yield of (3-CycloL hexyl - 3 - oxy - 3-phenylpropyl) - dimethylsulfonium iodide from the F. = 134 to 139 ° (gas evolution) is 48 parts (77%). After recrystallization from about 68 parts of ethanol 42 parts of white crystals with a mp = 138 to 140 ° obtain.

Example 2 Following the general procedure according to Example 1, the products listed in the table below were obtained using the suitable S-substituted 3-mercaptopropanols (I) disubstituted in the l-position and the respective halides. In some cases, acetone or ether was used as a solvent in the reaction. When using the less reactive halides or sulfides, considerably longer reaction times were required than stated in Example 1 with about 24 hours. In two cases little or no excess halide was used. These deviations are indicated in the table. Product | Halide | Solution | F in ° C middle 1. (3-Cyclohexyl-3-oxy-3-phenylpropyl) -ethyl-methyl-methyl iodide (several weeks) none 116.5 sulfonium iodide 2. Allyl (3-cyclohexyl-3-oxy-3-phenylpropyl) methyl allyl iodide ether 106.5 bis sulfonium iodide 107.5 3. (3-Cyclohexyl-3-oxy-3-phenylpropyl) methyl propargyl bromide acetone 141.5 propargyl sulfonium bromide (slight excess) 4. Benzyl- (3-cyclohexyl-3-oxy-3-phenylpropyl) -methyl-benzyl bromide acetone 105 bis sulfonium bromide 106 5. (3-Cyclohexyl-3-oxy-phenylpropyl) diethyl ethyl iodide (several weeks) ether 112 bis sulfonium iodide 113 6. p-Chlorophenacyl- (3-cyclohexyl-3-oxy-3-phenylpropyl) - p-Chlorophenacyl bromide methanol 127 bis methyl sulfonium bromide (10 0 / o excess) 128 Example 3 Isopropyl magnesium iodide in an ethereal solution is prepared in a conventional manner from 6.1 parts of magnesium and 42.4 parts of isopropyl iodide. 45 parts of α-methyl mercaptopropiophenone in 210 parts of ether are added to this solution, while stirring, and stirring is continued overnight at room temperature.

After adding a solution of 30 parts of ammonium chloride in 1000 parts Water is stirred under reflux for a further 3 hours. The essential solution will separated from the aqueous phase, washed a few times with water and over anhydrous Dried sodium sulfate. The ether is distilled off and leaves a yellowish color Oil, which in the distillation under reduced pressure after a small forerun 31.4 g of a product which passes over at Kr 0.6 = 125 to 135 °.

This product is contaminated with unreacted ketone 3-methyl mercapto l-phenyl- l-isopropylpropanol- (l). The pollution is caused by the following measures eliminated.

A solution of 10 parts of impure carbinol in 32 parts of methanol is with a solution of 6.8 parts of semicarbazide hydrochloride and 8.2 parts of sodium acetate .3 H2O mixed in 20 parts of water. After refluxing for 21/2 The solvent is removed under reduced pressure for hours. After adding water it becomes the mixture extracted with ether. The combined ether extracts are mixed with water washed and dried over anhydrous calcium sulfate. By filtering it off considerable amounts of fl-methylmercapto-propiophenone-semicarbazone in the form of separated hard, granular gray crystals insoluble in water and ether. To Filtering off the calcium sulfate will direct the ethereal solution of the carbinol used to make the sulfonium salt.

This ethereal solution is mixed with 18 parts of methyl iodide. After standing overnight at room temperature, a yellow solid substance is obtained.

Repeated recrystallization from alcohol gives 3-isopropyl -3 -oxy- 3-phenyl-propyl-dimethylsulfonium iodide as white crystals of F. = 123 to 126 ".

Example 4 4.1 parts of magnesium and 26.2 parts of bromobenzene are made in the usual way an ethereal solution of phenylmagnesium bromide is made. The solution is stirred with 30 parts of p-methyl mercaptopropiophenone in 70 parts Aether is added and stirring is continued overnight at room temperature. Then one will Solution of 25 parts of ammonium chloride in 250 parts of water are added and the mixture is stirred Continued under reflux for 3 hours. puts. The ether solution is from the aqueous phase separated, washed several times with water and over anhydrous sodium sulfate dried. The ether is removed by distillation and leaves 38 parts (84 ° / o) 1,1-Diphenyl-3-methyl-mercaptopropanol- (1) as a white crystalline product from F. = 108 °. Repeated recrystallization from absolute alcohol provides a Product of the F. = 109 °.

7 parts of 1, 1-diphenyl-3-methylmercaptopropanol- (1) are in the just required amount of anhydrous acetone and dissolved with 23 parts of methyl iodide offset.

The solution is left to stand in the dark at room temperature overnight. The precipitated product is filtered off, washed with anhydrous ether and air dried. There are 11.3 parts of dimethyl (3,3-diphenyl-3-oxypropyl) sulfonium iodide obtained as white crystals of F. = 1350 (decomposition). By recrystallization 8.8 parts (81%) of substance with a melting point of 138.5 ° (decomposition) are obtained from absolute methanol won.

Example 5 From 4.4 parts of magnesium and 30.9 parts of freshly distilled Benzyl bromide is an essential solution made from benzyl magnesium bromide. 35 parts of B-ethyl mercaptopropiophenone are added to this solution with vigorous stirring given in 350 parts of anhydrous ether. Stirring is done overnight at room temperature continued.

After adding a solution of 22 parts of ammonium chloride in 500 parts Water is stirred under reflux for 2 hours. The essential solution is provided by the separated aqueous phase, washed a few times with water and dried over anhydrous Dried sodium sulfate. Remain after the solvent has been distilled off 44 parts of a yellow colored oil, which in the distillation after a considerable Prerun 16 parts of l-phenyl-1-benzyl-3-ethylmercapto-propanol (1) provides the under Pass 1 mm pressure at 170 to 200 °. After standing for several days at room temperature the product crystallizes to a low-melting solid substance.

Repeated distillation of the crude product yields a material from Kr 0.3 = 157 to 158 ".

5 parts of 1-phenyl-1-benzyl-3-äthylmercaptopropanol- (1) are in 46 parts of methyl iodide dissolved; the solution is left overnight in the dark at room temperature ditched. The material, which separates out in the form of white crystals, becomes with washed with anhydrous ether and air dried. The product is used in the least possible Dissolved amount of absolute methanol, filtered off and with an excess of anhydrous Ether fell again. There are 5.3 parts of ethyl (3-phenyl-3-benzyl-3-oxypropyl) methylsulfonium iodide obtained from the F. = 115.5 ° (decomposition).

Claims (3)

PATENT CLAIMS: 1. Process for the preparation of γ-oxypropylsulfonium halides of the general formula wherein R1 is an aryl radical, R2 is a cycloalkyl, alkyl, aryl or aralkyl radical, R3 is an alkyl radical, R4 is an alkyl, aralkyl, alkenyl, alkynyl or phenacyl radical and X is a halogen atom, characterized in that one in l -Position disubstituted, S-substituted 3-mercaptopropanol- (1) of the general formula is reacted with an organic halide of the general formula R4 X, where R ,, R2, R3, R4 and X have the meaning given in the introduction. 2. The method according to claim 1, characterized in that the implementation is carried out in the presence of an excess of the organic halide. 3. The method according to claim 1 or 2, characterized in that those, disubstituted in the l-position, S-substituted 3-mercaptopropanols (1) of the formula II are used as starting compounds, which are obtained by reacting a jB-substituted mercaptopropionitrile of the Formula R3S-CH2-CH2-CN (1V) and a Grignard reagent of the formula RlMgHal prepared p-substituted mercaptopropiophenones of the general formula are obtainable with a Grignard reagent of the formula R2MgHal, where R1, R2 and R3 have the meaning given in claim 1 and Hal is a halogen atom. Publications considered: Reports of the German chemical Gesellschaft, Vol. 82 [1949], pp. 426 and 430; Journal of the American Chemical Society, Vol. 73 [1951], p. 5905; Helvetica Chimica Acta, Vol. 27 [1944], pp. 1209-1224.